Theanaphthoquinone inhibits fatty acid synthase expression in EGF-stimulated human breast cancer cells via the regulation of EGFR/ErbB-2 signaling

Toxicol Appl Pharmacol. 2007 Jan 15;218(2):107-18. doi: 10.1016/j.taap.2006.10.021. Epub 2006 Nov 10.


Fatty acid synthase (FAS) is a major lipogenic enzyme catalyzing the synthesis of long-chain saturated fatty acids. Most breast cancers require lipogenesis for growth. Here, we demonstrated the effects of theanaphthoquinone (TNQ), a member of the thearubigins generated by the oxidation of theaflavin (TF-1), on the expression of FAS in human breast cancer cells. TNQ was found to suppress the EGF-induced expression of FAS mRNA and FAS protein in MDA-MB-231 cells. Expression of FAS has previously been shown to be regulated by the SREBP family of transcription factors. In this study, we demonstrated that the EGF-induced nuclear translocation of SREBP-1 was blocked by TNQ. Moreover, TNQ also modulated EGF-induced ERK1/2 and Akt phosphorylation. Treatment of MDA-MB-231 cells with PI 3-kinase inhibitors, LY294002 and Wortmannin, inhibited the EGF-induced expression of FAS and nuclear translocation of SREBP-1. Treatment with TNQ inhibited EGF-induced EGFR/ErbB-2 phosphorylation and dimerization. Furthermore, treatment with kinase inhibitors of EGFR and ErbB-2 suggested that EGFR/ErbB-2 activation was involved in EGF-induced FAS expression. In constitutive FAS expression, TNQ inhibited FAS expression and Akt autophosphorylation in BT-474 cells. The PI 3-kinase inhibitors and tyrosine kinase inhibitors of EGFR and ErbB-2 also reduced constitutive FAS expression. In addition, pharmacological blockade of FAS by TNQ decreased cell viability and induced cell death in BT-474 cells. In summary, our findings suggest that TNQ modulates FAS expression by the regulation of EGFR/ErbB-2 pathways and induces cell death in breast cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / ultrastructure
  • Cell Survival / drug effects
  • Down-Regulation / physiology
  • Epidermal Growth Factor / pharmacology*
  • ErbB Receptors / genetics*
  • Fatty Acid Synthases / antagonists & inhibitors*
  • Female
  • Flow Cytometry
  • Genes, erbB-2 / genetics*
  • Humans
  • Immunoprecipitation
  • Naphthoquinones / pharmacology*
  • Oncogene Protein v-akt / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Stimulation, Chemical
  • Translocation, Genetic
  • Tyrosine / metabolism
  • fas Receptor / biosynthesis


  • Naphthoquinones
  • Sterol Regulatory Element Binding Protein 1
  • fas Receptor
  • theanaphthoquinone
  • Tyrosine
  • Epidermal Growth Factor
  • Fatty Acid Synthases
  • Phosphatidylinositol 3-Kinases
  • ErbB Receptors
  • Oncogene Protein v-akt